We identified mutations in the Ca2+-sensing receptor gene in patients with hypoparathyroidism. We have demonstrated that these mutations can either cosegregate with the disease in families with an autosomal dominant inheritance pattern or can arise de novo in patients with sporadic disease. When expressed in cultured cells, these mutations caused activation of the receptor by increasing the sensitivity to calcium and increasing maximal signal transduction capacity.We have also studied the regulation of mammalian longitudinal bone growth. We showed that fasting rapidly decreases longitudinal bone growth and growth plate width in vivo. This growth inhibition does not appear to be mediated by the local, growth plate insulin-like growth factor-I (IGF-I) system which was up-regulated. Instead it was associated with down-regulation of the systemic IGF-I system.Growth plate cartilage and the adjacent bone exhibit spatial polarity. By manipulating the spatial relationships within the growth plate, we have shown that the polarity of growth plate cartilage is determined by intrinsic factors. The cartilage polarity then determines the polarity of the adjacent bone and, consequently, the functional polarity of longitudinal bone growth. Other studies explore the role of fibroblast growth factor-2, retinoids, C-type natiuretic peptide, and cGMP in the regulation of cell proliferation and differentiation in the growth plate.Treatment trials using growth hormone or IGF-I for the treatment of extreme short stature are underway. We are beginning an additional clinical trial using alendronate, an inhibitor of bone resorption, to treat pediatric osteoporosis.